The global goal of this project is to assess how physicochemical characteristics of nanomaterials modulate biological environmental responses. In this application the influence of porosity, degradation and curvature of silica nanoparticles (SNPs) on mechanisms of cellular uptake, biodistribution, pharmacokinetics and toxicity will be examined. Specifically, we will examine in more detail the cellular fate and mechanisms of intracellular transport of the SNPs, how inflammatory responses are initiated in response to the changes in the physicochemical properties, and what would be the biological fate of degradation products of SNPs. Three Specific Aims are proposed: 1) 1. Synthesis and characterization of SNPs with systematic differences in size, porosity, surface roughness and functionality, and biodegradability, 2) Investigate how surface properties affect protein and cellular inflammatory mediated mechanisms in vitro, 3) Investigate chronic inflammatory mediated mechanisms as a function of surface properties in vivo.